Nitric oxide synthase inhibition in humans reduces cerebral blood flow but not the hyperemic response to hypercapnia.
OBJECTIVE
Animal studies suggest that nitric oxide (NO) is important in basal cerebral blood flow (CBF) regulation and that it may mediate the vasodilatory response to carbon dioxide. We investigated its role in the human circulation using the NO synthase inhibitor N(G)-monomethyl-L-arginine (L-NMMA).


METHODS
L-NMMA was administered as an intravenous bolus at three doses (1, 3, and 10 mg/kg). CBF was assessed by color velocity ultrasonic imaging of internal and common carotid artery volume flow (ICA flow and CCA flow) and transcranial Doppler ultrasound measurement of middle cerebral artery flow velocity (MCAv). The pressor effect of L-NMMA was controlled for by comparison with noradrenaline titrated to effect an equivalent blood pressure elevation.


RESULTS
L-NMMA produced a dose-dependent reduction in basal mean+/-SD CCA flow from 415.2+/-51.9 to 294+/-56.2 mL/min (at 10 mg/kg) and ICA flow from 268.8+/-59.4 to 226.2+/-72.6 mL/min (P<.005 and P<.05, respectively, comparing areas under the dose-response curve). This was reversed by L-arginine. Mean+/-SD systemic blood pressure rose from 85.2+/-6.4 to 100.8+/-9.6 mm Hg (P<.01). There was no significant reduction in MCAv. There was no significant change in the CBF response to either 6% or 8% carbon dioxide after L-NMMA. Noradrenaline produced a lesser fall in basal CCA flow (12.0%) but had a similar effect on the hypercapnic response.


CONCLUSIONS
Basal NO release is important in controlling human CBF, but intravenously administered L-NMMA does not inhibit the hypercapnic hyperemic response in humans. The discrepancy between CBF and MCAv after L-NMMA administration is consistent with MCA vasoconstriction. Neuronal NO synthase inhibition may be protective in stroke. However, our results suggest that nonselective NO synthase inhibitors such as L-NMMA should be used with caution because they reduce CBF.
White
R P
RP
Department of Clinical Neurosciences, King's College School of Medicine and Dentistry and the Institute of Psychiatry, London, UK.
Deane
C
C
Vallance
P
P
Markus
H S
HS
D000328:Adult; D001775:Blood Circulation / Q000187:drug effects*; D002245:Carbon Dioxide / Q000097:blood*; D002339:Carotid Arteries / Q000000981:diagnostic imaging / Q000187:drug effects / Q000502:physiology*; D017536:Carotid Artery, Common / Q000502:physiology / Q000648:ultrastructure; D002343:Carotid Artery, Internal / Q000502:physiology / Q000648:ultrastructure; D002560:Cerebrovascular Circulation / Q000187:drug effects*; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000494:pharmacology; D005260:Female; D006801:Humans; D006940:Hyperemia; D007275:Injections, Intravenous; D008297:Male; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors*; D009638:Norepinephrine / Q000008:administration & dosage / Q000494:pharmacology; D014463:Ultrasonography; D019323:omega-N-Methylarginine / Q000008:administration & dosage / Q000494:pharmacology*
D004791:Enzyme Inhibitors; D002245:Carbon Dioxide; D019323:omega-N-Methylarginine; D019001:Nitric Oxide Synthase; D009638:Norepinephrine